Despite the advent of highly active anti-retroviral therapy (HAART), HIV-1 associated dementia (HAD) continues to be a significant healthcare problem. HAD elicits a cascade of events in the CNS that result in a devastating loss of neuronal function and cognitive deterioration. We posit that the disease process occurs in a stepwise fashion, thus providing opportunity for the development of therapeutics directed at discrete pathogenic mechanisms. This application seeks to elucidate these mechanisms, identify small molecules to interdict this sequence and to evaluate their efficacy in models of HAD. The overall goals of this program project are to design rational therapeutic strategies to ameliorate HAD, and rapidly bring promising agents to Phase-I trials in a well-defined cohort of patients at risk for HAD. We propose to do this as follows: the Administrative Core A will coordinate data from all studies, and ensure that at least two clinical trials are performed during this award. Project 1 will test the hypothesis that activation of glycogen synthase kinase (GSK)-3beta may contribute to neuronal death and damage in the context of HAD; this project will also conduct experiments aimed at the development of novel inhibitors for GSK-3beta. Project 2 will target therapeutic strategies to prevent HIV- 1 neurotoxins from interfering with dopaminergic neurotransmission, which in turn induces Parkinson-like symptoms. Project 3 will exploit the ability of neurotrophic agents to activate nuclear factor kappa B (NFKB) in neurons to provide neuroprotection from HIV- 1 neurotoxins. Core B will then administer drugs (identified in Projects 1-3) + HAART to SCID mice that have received subcortical injections of HIV-1-infected mononuclear phagocytes. Brain metabolic (MRI spectroscopy, MRS) and behavioral assays will quantify protective effects of therapy in these mice, and pharmacokinetic (PK) assays will determine brain and serum levels of therapeutic agents and potential drug interactions with HAART. Based on results from Projects 1-3 and Core B patients in Project 4 receiving neuroprotective agents will first undergo PK studies, followed by Phase I safety and tolerability trials. Patients will primarily be enrolled from a well-characterized cohort at risk for HAD. Assessment of cognitive, functional and brain MRS parameters will also be performed. Results from the most promising trials will be disseminated to NARC, ACTG and industry for larger trials to assess efficacy.